Parkinson's disease is a neurological disorder characterized by a deficiency of dopamine (3,4-dihydroxyphenylethylamine), particularly in the basal ganglia. The clinical features of Parkinsonism include tremor, bradykinesia, rigidity and disturbance of posture. Presently, Parkinson's disease is most commonly treated by administering a drug such as levodopa (L-Dopa) which improves skeletal muscle function by being decarboxylated to dopamine and acting on the central nervous system (CNS).
L-Dopa (L-3,4-dihydroxyphenylalanine), the metabolic precursor of dopamine, is a commonly administered dopaminergic drug. L-Dopa is also formed in the body from L-tyrosine. L-Dopa has the ability to permeate striatal tissue, where it is converted to dopamine. However, orally administered dopamine cannot cross the blood-brain barrier. Because L-dopa is decarboxylated in the peripheral circulation, large doses are generally needed to result in accumulation of dopamine in the brain unless the L-dopa is administered in conjunction with a second drug, such as carbidopa, to block decarboxylation outside the brain. The majority of patients with Parkinson's disease who are treated with L-dopa ultimately develop side effects such as dyskinesias and psychiatric disturbances. Some patients do not respond to L-Dopa. As a result, there is a concerted effort to develop substitute therapies for dopamine-dependent CNS disorders, such as Parkinsonism.
Thyrotropin-releasing hormone (TRH) is a tripeptide (L-pyroglutamyl-L-histidyl-L-prolineamide) which occurs in the hypothalamus and influences the release of thyroid-stimulating hormone and prolactin from the pituitary gland. Due to its action on the pituitary gland, TRH has been reported to affect behavior in man and has been proposed for the treatment of depression. There have also been reports of TRH-induced increase in norepinephrine metabolism in the brain, which is due to TRH activation of tyrosine hydroxylase (TH), the enzyme of the rate-limiting step in the conversion of tyrosine to L-dopa in catecholamine synthesis. Some studies of intraperitoneal administration of TRH in mice demonstrate a marked increase of L-dopa accumulation in the brain and adrenals, indicating activation of in vivo tyrosine hydroxylase by TRH. However, it is not generally believed that TRH has this affect, because it has not been thought that TRH readily crosses the blood-brain barrier.
The amino acid tyrosine is the precursor of catecholamine biosynthesis in all nerve cells which produce catecholamines. Tyrosine is converted to L-dopa by the rate-limiting enzyme tyrosine hydroxylase. Tyrosine has been shown to increase or decrease blood pressure depending on the original levels, reduce depression and treat and prevent ventricular fibrillation.
Wurtman et al. reported (Science 185: 183-184, Jul. 12, 1974) increases in brain tyrosine concentrations results in increases in brain DOPA concentrations It had previously been thought that changes in brain tyrosine levels would not affect tyrosine's conversion to L-dopa because of the rate-limiting enzyme tyrosine-hydroxylase. A method of treating Parkinsonism and other related CNS disorders which alleviates the effects of the condition and does not have the limitations of presently available methods would be very valuable.